APROTININ

3).

Adult:

Owing to the risk of allergic/anaphylactic reactions, a 1ml (10,000 KIU) test dose should be administered to all patients at least 10 minutes prior to the remainder of the dose. After the uneventful administration of the 1ml test dose, the therapeutic dose may be given.

A H1 antagonist and a H2 antagonist may be administered 15 minutes prior to the test dose of aprotinin. 4). A loading dose of 1 - 2 million KIU is administered as a slow intravenous injection or infusion over 20 - 30 minutes after induction of anaesthesia and prior to sternotomy.

A further 1 - 2 million KIU should be added to the pump prime of the heart-lung machine. To avoid physical incompatibility of aprotinin and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to assure adequate dilution prior to admixture with the other component.

The initial bolus infusion is followed by the administration of a continuous infusion of 250,000 - 500,000 KIU per hour until the end of the operation. In general, the total amount of aprotinin administered per treatment course should not exceed 7 million KIU.

Paediatric population The safety and efficacy in children below 18 years of age have not been established. Renal impairment Available clinical experience suggests that patients with decreased renal function do not require special dose adjustment.

Hepatic impairment No data are available on dosage recommendations for patients with hepatic dysfunction. Elderly Reported clinical experience has not identified differences in responses in elderly patients. Method of administration Aprotinin should be infused using a central venous catheter.

The same lumen should not be used for the administration of any other medicinal product. When using a multi-lumen central catheter a separate catheter is not required. Aprotinin must be given only to patients in the supine position and must be given slowly (maximum 5 - 10ml/min) as an intravenous injection or a short infusion.

Summary of the safety profile The safety of aprotinin has been evaluated in more than forty five phase II and phase III studies including more than 3800 patients exposed to aprotinin. In total, about 11% of aprotinin-treated patients experienced adverse reactions.

The most serious adverse reaction was myocardial infarction. The safety of aprotinin has been monitored in the NAPaR between February 2016 and November 2020. 1%. The adverse reactions should be interpreted within the surgical setting.

Tabulated summary of adverse reactions Adverse drug reactions (ADRs) based on all placebo-controlled clinical studies with aprotinin sorted by CIOMS III categories of frequency (aprotinin n=3817 and placebo n=2682; status: April 2005) and based on the NAPaR are listed in the table below: Frequencies are defined as: Common: ≥1/100 to <1/10 Uncommon: ≥1/1,000 to <1/100 Rare: ≥1/10,000 to <1/1,000 Very rare: <1/10,000 Not known: cannot be estimated from the available data MedDRA Standard System organ class Common Uncommon Rare Very Rare Immune system disorders Allergic reaction Anaphylactic / anaphylactoid reaction Anaphylactic shock (potentially life threatening) Blood and lymphatic system disorders Disseminated intravascular coagulation, Coagulopathy Cardiac disorders Myocardial ischaemia, Coronary occlusion / thrombosis, Myocardial infarction, Pericardial effusion Vascular disorders Thrombosis, Embolic stroke Arterial thrombosis (and its organ specific manifestations that might occur in vital organs such as kidney, lung or brain), Pulmonary embolism Renal and urinary disorders Oliguria, acute kidney injury, Renal tubular necrosis General disorders or administration site conditions Injection and infusion site reactions, Infusion site (thrombo-) phlebitis Investigations Blood creatinine increased • ADRs derived from post-marketing reports are printed in bold italic Description of selected adverse reactions Allergic/anaphylactic reactions are rare in patients with no prior exposure to aprotinin.

In case of re-exposure the incidence of allergic/anaphylactic reactions may reach the five percent level. 9% for re- exposures greater than 6 months). A retrospective review suggests that the incidence of severe anaphylactic reactions to aprotinin may further increase when patients are re-exposed more than twice within 6 months.

Even when a second exposure to aprotinin has been tolerated without symptoms, a subsequent administration may result in severe allergic reactions or anaphylactic shock with, in very rare cases, fatal outcome.

The symptoms of allergic/anaphylactic reactions may include:

Respiratory system: asthma (bronchospasm) Cardiovascular system: hypotension Skin and appendages: pruritus, rash, urticaria Digestive system: nausea If allergic reactions occur during injection or infusion, administration should be stopped immediately.

e. adrenaline/epinephrine, volume substitution and corticosteroids. 98% between the groups (aprotinin n=3817 and placebo n=2682; status: April 2005). A trend of increased incidence of MI in association with aprotinin was observed in some studies, while other studies showed a lower incidence compared to placebo.

4. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme in UK.

uk/yellowcard

Aprotinin should not be used when CABG surgery is combined with another cardiovascular surgery because the benefit risk balance of aprotinin in other cardiovascular procedures has not been established. Laboratory monitoring of anticoagulation during cardiopulmonary bypass Aprotinin is not a heparin-sparing agent and it is important that adequate anticoagulation with heparin be maintained during aprotinin-therapy.

The partial thromboplastin time (PTT) and activated partial thromboplastin time (APTT) are similar and become immeasurable with high doses of heparin. Therefore, APTT and PTT should not be used to monitor anticoagulation with heparin in patients undergoing cardiopulmonary bypass graft surgery.

In patients undergoing cardiopulmonary bypass graft surgery with aprotinin therapy, one of the following methods is recommended to maintain adequate anticoagulation: 1. Individualized heparin and protamine management should be considered to reduce postoperative coagulation abnormalities and bleeding complications in cardiac surgery with cardiopulmonary bypass (CPB).

Individualized heparin management or titration is based on computer-based heparin dosing systems, anti- Xa measurements or blood heparin measurements in addition to the Activated Clotting Time (ACT). Anti-Xa measurement and blood heparin measurements are unaffected by aprotinin and should be carried out following test-manufacturer’s notices.

2. In the absence of individual heparin dosing tools, it is recommended that ACT tests are performed at regular intervals based on institutional protocols, and heparin doses have to be given accordingly. The required target ACT is dependent on the type of activator and equipment used.

Elevations of kaolin and celite ACT are expected in aprotinin-treated patients during surgery, and in the hours after surgery. In patients undergoing cardiopulmonary bypass with aprotinin therapy, a minimal celite ACT of 750 seconds or kaolin ACT of 480 seconds is recommended to maintain anticoagulation, independent of the effects of haemodilution and hypothermia.

ACT tests using a mixture of activators should be carried out following test-manufacturer’s notices. Protamine management As the protamine test is unaffected by aprotinin in aprotinin treated patients the neutralisation of heparin by protamine after discontinuation of cardiopulmonary bypass should be carried out following test- manufacturer’s notices.

Graft Conservation Blood drawn from the aprotinin central infusion line should not be used for graft preservation. 8). Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also single case reports of anaphylaxis occurring upon re- exposure after more than 12 months.

Standard emergency treatment for allergic/anaphylactic reactions should be readily available during treatment with aprotinin. 2). The test dose of aprotinin should only be administered when facilities and equipment for handling acute anaphylactic reactions are available on-site.

Renal impairment Results from prior observational studies indicate that renal dysfunction could be triggered by aprotinin, particularly in patients with pre-existing renal dysfunction. 1). An increase in renal failure and mortality compared to age-matched historical controls has been reported for aprotinin-treated patients undergoing cardiopulmonary bypass with deep hypothermic circulatory arrest during operation of the thoracic aorta.

Careful consideration of the balance of risks and benefits is therefore advised before administration of aprotinin to patients with pre-existing impaired renal function or those with risk factors (such as concomitant treatment with aminoglycosides).

1. g, Karkouti 2006, Mangano 2006, Coleman 2007, Pagano 2008, Ngaage 2008, Karkouti, 2009). In these studies, aprotinin was usually administered to patients who had more risk factors for increased mortality before surgery than patients in the other treatment groups.

Most of the studies did not adequately account for these baseline differences in risk factors and the influence of these risk factors on the results is not known. Therefore interpretation of these observational studies is limited and an association between aprotinin use and increased mortality can neither be established nor refuted.

Thus, aprotinin should only be used as authorized in isolated CABG surgery, after careful consideration of the potential risks and benefits. A publication by Fergusson et al. in 2008 analysed data from a randomised controlled trial, Blood Conservation Using Antifibrinolytics in a Randomised Trial (BART), and reported a higher mortality rate in aprotinin-treated patients compared to those treated with tranexamic acid or aminocaproic acid.

However, due to several methodological deficiencies no firm conclusion on cardiovascular risks can be made on the BART study results. In a post-authorization safety study (The Nordic […]

1. Patients with a positive aprotinin-specific IgG antibody test are at an increased risk of anaphylactic reaction when treated with aprotinin. Therefore, administration of aprotinin is contraindicated in these patients. In case no aprotinin specific IgG antibody test is possible prior to treatment, administration of aprotinin to patients with a suspected previous exposure including in fibrin sealant products during the last 12 months is contraindicated.